The neutral noncyclic, lithium-selective ionophore ETH1644, which is structurally different from previously available ionophores of this type, is a selective carrier of Li+ in lipid bilayer membranes of various lipid composition. The ionophore forms a 2:1 carrier/cation complex, and the rate-limiting step in the overall transport process is the diffusion of the carrier/ion complex across the membrane. The selectivity sequence for lithium vs. other ions normally found in biological systems is: Li+ (1) greater than Na+ (0.017) greater than or equal to K+ (0.017) greater than Cl- (0.001), Ca2+ and Mg2+ are impermeant. At neutral pH protons do not interfere with the Li+-carrying ability of this ionophore. On the basis of structural differences and supported by conductance data, it is argued that the improved selectivity of Li+ over the other alkali cations is due more to a decrease in the affinities of the ionophore for the latter cations that to an increase of its affinity to Li+. This ionophore can also act as a carrier of biogenic amines (catecholes, indoles and derivatives), with the structure of the permeant species and mechanism of permeation similar to that observed with the alkali cations. The selectivity sequence is: tryptamine (18.1) greater than phenylethylamine (11.6) greater than tyramine (2.4) greater than Li+ (1) greater than serotonin (0.34) greater than epinephrine (0.09) greater than dopamine (0.05) greater than norepinephrine (0.02), showing the ionophore to be more selective to Li+ than to any of the neurotransmitters studied.

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The neutral, noncyclic Li(+)-selective ionophore ETH1810, which is a di-imide, differs structurally from previous similar ionophores by removal of the intramolecular symmetry of the N-imide substituents. Properties of this ionophore, as a potential carrier of lithium, were probed through studies of ionophore-induced changes in electrical properties of lipid bilayer membranes. ETH1810 was found capable of transporting lithium and other monovalent cations, across lipid bilayer membranes, forming 2:1 ionophore:ion membrane-permeating species. It was found to be 10-fold more potent than ETH1644, which was the previous best ionophore of this type. The selectivity sequence among alkali cations was found to be: Li+ (1) greater than Na+ (0.009) greater than K+ (0.004) greater than Cs+ (0.0035). Among the physiological alkali cations, it constitutes a 40 (vs. Na+) to 160% (vs. K+) improvement over ETH1644. ETH1810 was also found to be capable of acting as a carrier of biogenic amines and related molecules, with the following selectivity sequence:tryptamine (20) greater than phenylethylamine (7.8) greater than tyramine (4.3) greater than serotonin (2.5) greater than Li+ (1) greater than NH+4 (0.013) greater than dopamine (0.012). It was found that protons, at physiological concentrations, do not interfere with the lithium transport mediated by ETH1810. The relationship between the improvements in ionic selectivity and potency vs. the differences in structural features is discussed.

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